Interleukin-16 (IL- 16) is a structurally unique cytokine that uses CD4 as a receptor to signal diverse biological activities in target cells including but not limited to T cells, monocytes, dendritic cells and eosinophils. Initially described as a chemoattractant factor for CD4+ T cells, IL-16 was later found to upregulate IL-2Rcz and HLADR expression, and to cause reversible anergy of CD4+ T cells in vitro. A role for IL-16 in pathological immune responses is suggested by its presence in a variety of diseases characterized by CD4+ T cell accumulation including asthma, sarcoidosis, inflammatory bowel disease, and rheumatoid arthritis. In some disease states, epithelial cells or fibroblasts express IL-16. A role for IL-16 in host defense is suggested by elevated blood levels in HIV-infected hosts, and by its expression in tuberculous granulomas. The biological activities described for IL-16 in vitro suggest that it could function either as a pro-inflammatory or anti-inflammatory cytokine in vivo. We cloned the murine IL-16 gene and used it to create an IL- 16 knockout mouse. In this application, we propose to challenge the IL-16 knockout mouse by experimental infection with Cryptococcus neoformans to learn how IL-16 functions within the integrated immune response in vivo. Preliminary data suggest that IL-16-/- mice fail to control pulmonary C. neoformans infection despite mounting an exuberant inflammatory response. We will investigate the specific deficits displayed by IL-16-/- mice in both the T cell and macrophage components of cell-mediated immunity, and we will examine the role of IL-16 expression by bronchial epithelial cells in host defense. Our research plan capitalizes on a well-characterized mouse model of cryptococcal infection that provides an excellent basis to study normal and abnormal cell mediated immune responses in the lung. The project will contribute new basic knowledge about the role of IL-16 in immunity, and it will provide additional understanding of protective immunity against the important AIDS co-pathogen C. neoformans.